Efficacy Of Different Dosage Regimens Of Carbimazole In The Treatment Of Primary Hyperthyroidism.

OBJECTIVES: To compare the efficacy of Single dose with Divided dose regimen of Carbimazole for the induction of Euthyroidism in hyperthyroid patients. METHODS: All consecutive hyperthyroidism patients from December 2018 to December 2019 fulfilling the inclusion criteria were included. They were allocated randomly into 2 groups: Group A - single dose of Carbimazole (OD-CMZ) and Group B - divided dose of Carbimazole (DD-CMZ). The therapeutic efficacy was measured at regular intervals (every 4 weeks) for 6 months. Their demographics and therapeutic management were analysed. RESULTS: Of a total of 69 (n=34 in Group A, n=35 in Group B) patients, there was no significant difference in baseline concentrations of TSH and T4 as well as their cumulative rate of reductions (p-value, 0.023). Furthermore, no difference in achieving euthyroidism was noted at follow-up visits between Group A and B respectively ([0:0%; p-value 1.00, month 1], [70.6:74.3%; p value 0.22, month 2], [85.3:85.7%; p value 0.39, month 3], 97.1:82.9%; p-value 0.23, month 4], [100:91.4%; p-value 0.29, month 5], [100:100%%; p value 1.00, month 6] at monthly intervals. Cases of Hypothyroidism were reported more in the DD-CMZ (14.3%) and the difference was statistically significant (p-value 0.003). CONCLUSIONS: Due to no significant difference in the efficacy and more chances of getting hypothyroid in divided dose regimen, we conclude that single dose regimen is more effective method for treating hyperthyroidism.

Safety of antithyroid drugs in pregnancy: update and therapy implications.

Introduction: The thionamide antithyroid drugs, methimazole (MMI), its pro-drug derivative carbimazole (CMZ), and propylthiouracil (PTU) are the mainstay of treatment for hyperthyroidism in pregnancy. However, antithyroid drugs carry risks of adverse effects that can affect fetal and maternal well-being.Areas covered: This review provides an update on the safety of antithyroid drugs in pregnancy, focusing on the most serious concerns of severe liver disease and congenital anomalies.Expert opinion: PTU-induced liver disease is uncommon but can run a catastrophic course in pregnancy with a risk of liver failure and threats to maternal or fetal survival. Acute pancreatitis is a relatively rare occurrence that has been linked to thionamide use in a handful of reports in non-pregnant individuals. Observational studies on the risk of birth defects with antithyroid drug exposure in pregnancy overall show an increase in birth defect risk with exposure to CMZ/MMI, and to a lesser extent, PTU. Further studies are required to determine whether the currently recommended approach of switching between thionamide drugs in pregnancy improves outcomes. Ultimately, a preventative strategy of offering definitive therapy to hyperthyroid women of childbearing potential offers the best approach to truly reduce the risks of antithyroid drug adverse effects in pregnancy.

Thyroid storm presenting as septic shock in the intensive care unit: A Case Series.

Thyroid storm is a rare endocrine emergency that rarely presents with septic shock. It occurs in thyrotoxic patients and is manifested by decompensation of multiple organs, triggered by severe stress. The diagnosis and response to treatment is made by Burch-Wartofsky point scale or Japanese thyroid association criteria due to lack of pathophysiology of thyroid storm. We reported series of patients that presented with altered sensorium, cough, fever, palpitation, shortness of breath and shock. Patient were treated initially for septic shock, later diagnosed as thyroid storm and was treated with oral carbimazole, propanolol and digoxin. From this, we want to emphasize that thyroid storm can have any presentation that should be kept in differential diagnosis of septic shock not responding to usual treatment; early diagnosis and treatment with oral medication can decrease morbidity and mortality in rural setting where intravenous form of antithyroid drug are not available for thyroid storm. Keywords: sepsis; septic shock; thyroid storm.

Serotonin syndrome unmasking thyrotoxicosis.

A 26-year-old cachectic man presented with an altered mental status. He was agitated, tremulous, hyperthermic and diaphoretic with largely dilated pupils. Collateral history revealed acute ingestion of 3,4-methylenedioxymethamphetamine on a background of chronic drug abuse. His condition deteriorated requiring sedation and intubation with transfer to the intensive care unit. A diagnosis of serotonin syndrome was made, based on his findings in keeping with the Hunter criteria, and he was treated with supportive management during a resultant and briefly sustained delirium. With gradual resolution of his agitated state, further questioning and blood work a concurrent, and potentially contributory, thyrotoxicosis was revealed. The patient was commenced on treatment for this with urgent outpatient follow-up with both a local otolaryngologist and endocrinologist for consideration of further treatment.

Thyrotropin receptor antibodies and a genetic hint in antithyroid drug-induced adverse drug reactions.

BACKGROUND: Antithyroid drugs (ATDs) are known to cause various adverse drug reactions (ADRs) that can lead to treatment complexity and unpredictable risks. With the aim of ensuring safer drug use, we assessed whether thyrotropin receptor antibody (TRAb) titers are associated with ATD-induced cutaneous reactions and/or hepatotoxicity, and examined potential genetic predisposition factors. METHODS: We compared TRAb titers of 37 Graves' disease (GD) patients who had experienced carbimazole/methimazole-induced cutaneous reactions and/or hepatotoxicity with those of 40 normal individuals, or 78 GD patients without the aforementioned ATD-induced ADRs. We performed a genome-wide association study and/or human leukocyte antigen genotyping on GD patients [first stage (chart reviews): 24 cases with ADRs and 423 controls; second stage (actively recruited): 45 cases with ADRs and 137 controls]. RESULTS: For patients with Graves' hyperthyroidism, individuals with higher TRAb titers showed a predisposition to carbimazole/methimazole-induced cutaneous reactions and/or hepatotoxicity, with an estimated odds ratio of 5.19 (cut-off value: 64%). Potential associations with the rs144542704 and rs61893841 on chromosomes 17 and 11, respectively, warrant further genetic association analysis. CONCLUSION: Our findings support the use of carbimazole/methimazole in patients with low TRAb titers to ensure safer drug use. The identified genetic associations warrant further research.

Evidence for the possible occurrence of Grave's disease in a blue-eyed black lemur (Eulemur flavifrons).

The blue-eyed black lemur (Eulemur flavifrons) is classified by the International Union for Conservation of Nature (IUCN) as critically endangered. A 23-year-old male housed at Mulhouse Zoo presented with lethargy, polyphagia, alopecia, and chronic weight loss. Clinical examination suggested an endocrine pathology such as hyperthyroidism. Secondary examinations included cervical ultrasound, thyroid biopsy, and scintigraphy. The latter revealed elevated thyroid activity. Blood analysis was performed to measure the level of anti-receptor thyroid-stimulating hormone antibodies, which allowed us to test the autoimmune hypothesis. The high level of antibodies together with levels of thyroid-stimulating hormone and the scintigraphy images led to the diagnosis of Grave's disease. Carbimazole treatment followed by thyroidectomy resulted in a quick weight gain and general improvement in health status. The following breeding season, the treated individual sired an offspring. To the authors' knowledge, this is the first report of likely Grave's disease in a non-human primate.

Long-term outcome of thyrotoxicosis in childhood and adolescence in the west of Scotland: the case for long-term antithyroid treatment and the importance of initial counselling.

BACKGROUND: Thyrotoxicosis is both rarer and more severe in children than in adults, rendering management difficult and often unsatisfactory. OBJECTIVE: To ascertain outcome in a geographically defined area of Scotland between 1989 and 2014. METHOD: Retrospective case note review with follow-up questionnaire to family doctors for patients with Graves' disease and Hashimoto's thyroiditis. RESULTS: Sixty-six patients (58 females:8 males) comprising 53 with Graves' disease and 13 with Hashimoto's thyroiditis were diagnosed at median 10.4 (2.9-15.8) years and followed up for 11.8 (2.6-30.2) years. Antithyroid drug (ATD) therapy was stopped electively in 35 patients after 4.5 (1.5-8.6) years, resulting in remission in 10/13 Hashimoto's thyroiditis and 10/22 Graves' disease. Side effects occurred in 12 patients receiving carbimazole, six of whom changed to propylthiouracil; no adverse events occurred in the latter patients.Second-line therapy was given to 37 patients (34 with Graves' disease), comprising radioiodine (22) at 15.6 (9.3-24.4) years for relapse (6), poor control/adherence (14) or electively (2); and surgery (16) at 12 (6.4-21.3) years for relapse (4), poor control/adherence (5) and electively (7). Adherence problems with thyroxine replacement were reported in 10/33 patients in adulthood. CONCLUSIONS: Hashimoto's thyroiditis should be distinguished from Graves' disease at diagnosis since the prognosis for remission is better. Remission rates for Graves' disease are low (10/53 patients), time to remission variable and adherence with both ATD and thyroxine replacement often problematic. We recommend (a) the giving of long-term ATD rather than a fixed course of treatment in GD and (b) meticulous and realistic counselling of families from the time of diagnosis onwards.

Hickam's dictum: Myasthenia Gravis presenting concurrently with Graves' disease.

We present two patients with Graves' disease and concurrent myasthenia gravis. The impact of the dual diagnosis on the clinical course and the potential for a delayed diagnosis of myasthenia gravis is discussed. Patient 1, a 28-year-old man was diagnosed with Graves' disease following his second respiratory arrest. His history was strongly suggestive of a second pathology. Patient 2, a 66-year-old Cantonese woman with established Graves' disease presented with thionamide-related neutropaenia. Examination revealed bilateral ptosis and right lateral rectus palsy. Both patients had thyrotoxicosis secondary to Graves' disease with concurrent myasthenia gravis. Although neuromuscular weakness is common in Graves' disease, coexisting myasthenia gravis (MG) is rare and can cause profound morbidity. Ocular signs in both diseases may cause diagnostic confusion although ptosis suggests coexisting MG. In both cases, the thyrotoxicosis delayed the diagnosis of MG.

Thyrotoxicosis in patients with hypothyroidism is not just overtreatment.

A 62-year-old Caucasian woman presented with hypothyroid symptoms and biochemical thyrotoxic picture. Previously, she underwent right-sided subtotal thyroidectomy and left partial thyroid lobectomy for thyroid lumps, and treated with thyroxine replacement for hypothyroidism. Although there were no significant findings on clinical examination, investigations confirmed thyrotoxicosis with positive autoimmunity against thyroid glandâ€"all in line with a diagnosis of Graves’ hyperthyroidism. We would like to highlight atypical presentations of thyroid dysfunction and conversion of underactive to overactive thyroid status with this case. Early recognition, diagnosis and intervention are essential to prevent and/or reduce associated morbidity and mortality. When encountered with such clinical conundrums, we recommend seeking opinion from an experienced endocrinologist while interpreting such situation.

Thyrotoxic periodic paralysis as an initial presentation of Graves' disease in a Saudi patient.

Thyrotoxic periodic paralysis (TPP) is a well-known complication of hyperthyroidism, characterised by recurrent flaccid paralysis with hypokalaemia. To date, only five cases of this rare disorder have been reported in Saudi Arabia. Here, we report an additional case involving a 25-year-old Saudi man who presented with lower limb paralysis and severe hypokalaemia. Clinically, he showed symptoms and signs suggestive of Graves' disease, which was confirmed by laboratory investigations. Carbimazole, a beta-blocker and potassium replacement were administered, resulting in dramatic improvement of the TTP. This case emphasises the importance of considering TPP in patients with acute muscle weakness and the importance of promptly initiating treatment and preventing relapse of TPP.

Thyrotoxic Channelopathies.

Thyrotoxic periodic paralysis (TPP), a disorder most commonly seen in Asian men, is characterized by abrupt onset of hypokalemia and paralysis. The condition primarily affects the lower extremities and is secondary to thyrotoxicosis. Early recognition of TPP is vital to initiating appropriate treatment and to avoiding the risk of rebound hyperkalemia that may occur if high-dose potassium replacement is given. Here we present a case of 31 year old male with thyrotoxic periodic paralysis with diagnostic and therapeutic approach.

HLA-B*38:02:01 predicts carbimazole/methimazole-induced agranulocytosis.

Thioamides antithyroid-drugs (ATDs) are important in hyperthyroid disease management. Identification of the susceptibility locus of ATD-induced agranulocytosis is important for clinical management. We performed a genome-wide association study (GWAS) involving 20 patients with ATD-induced agranulocytosis and 775 healthy controls. The top finding was further replicated. A single-nucleotide polymorphism (SNP), rs185386680, showed the strongest association with ATD-induced agranulocytosis in GWAS (odds ratio (OR) = 36.4; 95% confidence interval (CI) = 12.8-103.7; P = 1.3 × 10(-24)) and replication (OR = 37; 95% CI = 3.7-367.4; P = 9.6 × 10(-7)). HLA-B*38:02:01 was in complete linkage disequilibrium with rs185386680. High-resolution HLA typing confirmed that HLA-B*38:02:01 was associated with carbimazole (CMZ)/methimazole (MMI)-induced agranulocytosis (OR = 265.5; 95% CI = 27.9-2528.0; P = 2.5 × 10(-14)), but not associated with propylthiouracil (PTU). The positive and negative predictive values of HLA-B*38:02:01 in predicting CMZ/MMI-induced agranulocytosis were 0.07 and 0.999. Approximately 211 cases need to be screened to prevent one case. Screening for the risk allele will be useful in preventing agranulocytosis in populations in which the frequency of the risk allele is high.

Muscle paralysis in thyrotoxicosis.

Thyrotoxic periodic paralysis (TPP) is a condition characterised by muscle paralysis due to hypokalaemia usually secondary to thyrotoxicosis. We report a case of a 31-year-old man with no known comorbidities who presented to a tertiary healthcare unit with a 1-month history of difficulty in breathing, palpitations, weight loss and hoarseness of voice. On examination, his thyroid gland was palpable and fine hand tremors were present. An initial provisional diagnosis of hyperthyroidism was made. Three months after initial presentation, the patient presented in emergency with severe muscle pain and inability to stand. Laboratory results revealed hypokalaemia. All the symptoms reverted over the next few hours on administration of intravenous potassium. A diagnosis of TTP was established. After initial presentation, the patient was treated with carbimazole and propranolol. Once he was euthyroid, radioactive iodine ablation therapy (15 mCi) was carried out as definitive therapy, after which the patient's symptoms resolved; he is currently doing fine on levothyroxine replacement and there has been no recurrence of muscle paralysis.

[The occurrence of agranulocytosis due to antithyroid drugs in a cohort of patients with Graves disease treated with radioactive iodine 131I during 14 years]. / Výskyt agranulocytózy po tyreostaticích v kohorte pacientu s Gravesovou nemocí lécených radioaktivním jodem 131I v prubehu 14 let.

INTRODUCTION: Agranulocytosis is a serious complication of antithyroid drugs (ATD) treatment of thyrotoxicosis. The aim of our work was to assess the occurrence of agranulocytosis in Graves disease (GD) patients admitted for radioactive iodine 131I (RAI) treatment to our thyroid unit. PATIENTS AND METHODS: We analyzed retrospectively a cohort of 603 GD patients (500 women and 103 men; mean age 51.5 ± 12.7 years) who received RAI between 1999 and 2012. Of them, 327 (54 %) patients were originally treated with carbimazole (CBZ), 215 (36 %) with methimazole (MMI) and 61 (10 %) with propylthiouracil (PTU). RESULTS: Agranulocytosis due to ATD was the cause of RAI treatment in 7 patients of 603. All of them were women (mean age 48.7 years; range 23-78). In 4 patients, agranulocytosis occurred on MMI treatment, and in 3 patients on CBZ. After recalculation of CBZ to the equipotent dose of MMI, the mean ATD dose was 22.4 mg MMI/day (range 9-40). No agranulocytosis due to PTU was found in our cohort. The time from beginning ATD treatment to agranulocytosis was 20-41 days. In 5 patients there was a development of fever, while in 2 patients the complication was diagnosed from routine blood count. The mean duration of agranulocytosis was 5.9 days (range 4-8). CONCLUSION: Agranulocytosis incidence in our cohort of patients was 1.2 %, while in most reports the prevalence ranged from 0.2 to 0.5 %. In all patients, agranulocytosis occurred early, and in one third it was asymptomatic when found. The aim of our report is to bring attention to a relatively rare, but potentially serious, complication of ATD treatment.

Antithyroid drug-related hepatotoxicity in hyperthyroidism patients: a population-based cohort study.

AIMS: The evidence of hepatotoxicity of antithyroid drugs (ATDs) is limited to case reports or spontaneous reporting. This study aimed to quantify the incidence and comparative risks of hepatotoxicity for methimazole (MMI)/carbimazole (CBM) vs. propylthiouracil (PTU) in a population-based manner. METHODS: We conducted a cohort study of hyperthyroidism patients initially receiving MMI/CBM or PTU between 1 January 2004 and 31 December 2008 using the Taiwan National Health Insurance Research Database. The examined hepatotoxicity consisted of cholestasis, non-infectious hepatitis, acute liver failure and liver transplant, with the incidences and relative risks being quantified by Poisson exact methods and Cox proportional hazard models, respectively. RESULTS: The study cohort comprised 71 379 ATD initiators, with a median follow-up of 196 days. MMI/CBM vs. PTU users had a higher hepatitis incidence rate (3.17/1000 vs. 1.19/1000 person-years) but a lower incidence of acute liver failure (0.32/1000 vs. 0.68/1000 person-years). The relative risk analysis indicated that any use of MMI/CBM was associated with a 2.89-fold (95% CI 1.81, 4.60) increased hepatitis risk compared with PTU, with the risk increasing to 5.08-fold for high dose MMI/CBM (95% CI 3.15, 8.18). However, any MMI/CBM use vs. PTU was not related to an increased risk of cholestasis (adjusted hazard ratio [HR] 1.14, 95% CI 0.40, 3.72) or acute liver failure (adjusted HR 0.54, 95% CI 0.24, 1.22). CONCLUSIONS: MMI/CBM and PTU exert dissimilar incidence rates of hepatotoxicity. Compared to PTU, MMI/CBM are associated in a dose-dependent manner with an increased risk for hepatitis while the risks are similar for acute liver failure and cholestasis.

[The use of antithyroid drugs should be reduced as much as possible in the first trimester].

The treatment of choice for hyperthyroidism in pregnancy is antithyroid drugs, but the potential risk of birth defects is of major concern. For the use of thiamazole and carbimazole, there is consistent evidence of an increased risk of birth defects, which are often severe. For the use of propylthiouracil, the evidence is less clear. These birth defects may be less severe, and a Danish study which included all birth defects diagnosed before the age of two years showed an increased risk of birth defects in the face and neck region and in the urinary system after the use of propylthouracil.

The pharmacokinetics of methimazole in a novel lipophilic formulation administered transdermally to healthy cats.

AIM: To determine the pharmacokinetics of a novel lipophilic formulation of transdermal methimazole compared to oral carbimazole. METHODS: Healthy cats received 5 mg carbimazole orally every 12 hours for 13 treatments (n=6), then received transdermal methimazole (n=5) at a dose of 5 mg, then 10 mg, once daily on the pinna for 7 days, with 21 days between treatments. Concentrations of methimazole in serum over 24 hours and at 148 hours were determined by high performance liquid chromatography. RESULTS: Concentrations of methimazole in serum for the first 24 hours were not reliably detected in all cats treated with 5 mg methimazole transdermally, while for those receiving 5 mg carbimazole orally and 10 mg methimazole transdermally all cats had detectable concentrations of methimazole in serum. The maximum concentration and area under the curve were lower in cats receiving 10 mg methimazole transdermally (108 (SD 25) ng/mL and 2544 (SD 216) mg-hour/mL, respectively) than those receiving 5 mg oral carbimazole (355 (SD 113) ng/mL and 31,866 (SD 439) ng-hour/mL, respectively) (p<0.05). The time at maximal concentration and elimination half-life were longer for 10 mg transdermal methimazole (5.2 (SD 1.1) hours and 13 (SD 3) hours, respectively) compared to 5 mg oral carbimazole (2.1 (SD 1.6) hours and 5.1 (SD 1.2) hours, respectively). At 148 hours, mean concentrations of methimazole in serum were higher in cats receiving 10 mg methimazole transdermally (506 (SD 165) ng/mL) than for 5 mg oral carbimazole (255 (SD 28) ng/mL) or 5 mg transdermally (204 (SD 76) ng/mL). The mean relative bioavailability of 10 mg transdermal methimazole compared to oral carbimazole was 48 (min 43, max 55)%. CONCLUSION: Transdermal methimazole at a dose of 10 mg administered to the pinnae of healthy cats once daily in a novel lipophilic formulation has half the relative bioavailablity compared to 5 mg oral carbimazole. CLINICAL RELEVANCE: Transdermal methimazole can be absorbed from the skin of healthy cats.

Best practice for the pharmacological management of hyperthyroid cats with antithyroid drugs.

Pharmacological management of feline hyperthyroidism offers a practical treatment option for many hyperthyroid cats. Two drugs have been licensed for cats in the last decade: methimazole and its pro-drug carbimazole. On the basis of current evidence and available tablet sizes, starting doses of 2·5 mg methimazole twice a day and 10 to 15 mg once a day for the sustained release formulation of carbimazole are recommended. These doses should then be titrated to effect in order to obtain circulating total thyroxine (TT4) concentrations in the lower half of the reference interval. Treated cases should be monitored for side-effects, especially during the first months of treatment. Some side-effects may require discontinuation of treatment. At each monitoring visit, clinical condition and quality of life should also be evaluated, with special attention to possible development of azotaemia, hypertension and iatrogenic hypothyroidism. When euthyroidism has been achieved, monitoring visits are recommended after 1 month, 3 months and biannually thereafter. Cats with pre-existing azotaemia have shorter survival times. However, development of mild azotaemia during the initial course of treatment, unless associated with hypothyroidism, does not appear to decrease survival time. The long-term effects of chronic medical management require further study.